C-3- and C-4-Alkylated Polyhydroxypyrrolidines: Enantiospecific Syntheses and Glycosidase Inhibitory Activity

Short, efficient, and stereoselective syntheses of enantiomerically pure C-3- and C-4-alkylated analogues of (2 R,3 S,4 R )-3,4-dihydroxy-2-(hydroxymethyl)pyrrolidine, a potent α-galactosidase inhibitor, from 4-hydroxy- l -proline are presented. Grignard addition or enolate alkylation of a N -(9-phenylfluoren-9-yl)-4-oxo-3-[(methoxymethyl)oxy]proline and epoxidation or hydroboration of a 4-methylene-3-[(methoxymethyl)oxy]proline proceeded with complete stereoselection and in excellent yields. The inhibitory activities of the synthesized pyrrolidines were measured and showed that the fit of A. niger α-galactosidase and the jack bean α-mannosidase around C-3 of the pyrrolidine ring (α face) must be very tight, while the fit around C-4 (α face) is much looser. Positioning a methylene group between the hydroxyl at C-4 and the pyrrolidine ring completely abolishes the inhibitory activity (see analogue 5 ).